SummaryBackgroundWe designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma.MethodsEURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030.FindingsBetween April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78–1·23]); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate.InterpretationEURAMOS-1 results do not s...

This manuscript describes the experience from registration until randomisation for a cohort of 2260 patients with osteosarcoma who joined the EURAMOS-1 trial. This includes pre-operative chemotherapy and surgery. It sets out the practical issues in collaboration and in achieving randomisation.

The objective of this study was to evaluate the efficacy of 2-chlorodeoxyadenosine (2-CdA), a purine nucleoside analog, in treating recurrent Langerhans cell histiocytosis (LCH) in children. This study retrospectively analysed the clinical records of 13 patients who were seen in the department for recurrent LCH. These patients were treated consecutively with 2-CdA chemotherapy between July 1997 and May 2005. Median age at diagnosis was 4 years 7 months and median pre-treatment duration of disease was 16.4 months. Four children received 0.1 mg kg-1 per day for 7 days and nine patients 5 mg m-2 per day for 5 days, repeated every 21 days. The maximum number of courses of 2-CdA per patient was limited to six. Seventy-six courses of 2-CdA were administered without difficulty. All 13 patients (100%) had a clinical response documented by radiographic investigation. Nine patients did not require additional therapy and remain in complete remission (CR). Four remaining children are currently disease-free after receiving other therapy as irradiation (two cases) or maintenance chemotherapy (vinblastine, prednisone and 6-mercaptopurine) (one case) or chemotherapy (vinblastine) + irradiation (one child) ( Table I). Hematologic toxicity was minimal and no infectious complications were documented. Median follow-up after initiation of 2-CdA treatment was 4 years 3 months (range 7 months - 8 years 2 months). This experience confirms the reported efficacy of 2-CdA in the treatment of LCH. However, further studies are needed to determine the role of this agent in high-risk patient who did not achieve complete remission after 2-CdA administration.

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Langerhans cell histiocytosis (LCH) affecting child vulva alone is a very rare disease. Only 13 cases of primary vulvar LCH have been previously reported in the medical literature. We describe an additional case in which the LCH was confined to the vulva, with review of the literature. A 16.5-year-old girl presented with papulous and ulcerative lesions on her labia majora and minora. The biopsy revealed a typical histopathologic finding consistent with LCH. A metastatic work-up did not reveal any evidence of the disease except on the vulva. Treatment was carried out according to LCH II protocol. The patient was diagnosed with a recurrent disorder in the vulva 8 months after the completion of primary chemotherapy. For this reason, she underwent second line treatment with 2-chlorodeoxyadenosine. Eighteen months after the second line chemotherapy, the patient has no signs of a local or systemic recurrence. Primary LCH of vulva is very unusual, but we have to keep in mind this possibility when an adolescent girl presents with an atypical chronic lesion on the vulva. This patient appears to be the first case of adolescent 16.5 year old having a solely cutaneous lesion of the vulva.